Diabetes Prevention - Promise and Limitations: A Review

[publication pending]

Review Article

Diabetes Prevention - Promise and Limitations:

A Review Constantine Kaniklidis

European Association for Cancer Research (EACR) Director, Medical Research, No Surrender Breast Cancer Foundation

(NSBCF)

Correspondence: Constantine [email protected]

Date of last update: April 15, 2013.

Disclosures: The author indicates no financial relationships.

Abstract We are experiencing a pandemic in metabolic syndrome and in particular diabetes

and obesity, with an expected doubling of prevalence by 2025 – 2030 to between 366 - 380 million cases worldwide, and with over 8.3% of adults being affected in the

United States alone. But even more concerning is the fact that over 79 million American adults have a condition of “prediabetes,” with either impaired glucose

tolerance (IGT) or impaired fasting glucose (IFG) or elevated A1C, putting them at significantly increased 5 - to 15-fold higher risk of progression to frank

diabetes compared to people with normal blood glucose. This is an especially grave problem since treatment only prevents some of the dire complications of

diabetes, usually failing to restore normal blood glucose levels or to eliminate all of the adverse events associated with diabetes, entailing enormous and

accelerating national and global economic and social costs. Most regrettably the burden of diabetes continues to shift toward low and middle-income countries

where almost 80% of diabetes deaths occur, precisely where there is limited access to affordable treatment, and often insufficient education / awareness of

the magnitude and fundamentals of the problem. We here review and critically appraised the diabetes prevention research to date, restricting attention to

Kaniklidis, C. Diabetes Prevention – Promise, Limitations Review Copyright © 2013. Constantine Kaniklidis. All rights reserved.

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predominantly Level I (RCT, systematic review and meta-analyses) data, exposing certain misperceptions in our understanding of the problem and suggesting some

ways forward.

The Imperative for Prevention The pandemic of type 2 diabetes is an enormous

public health problem, with an expected doubling of prevalence to between 366 - 380

million cases projected by 2025 - 2030 worldwide [1,2] Currently the prevalence is

effectively epidemic in proportions, with more than 8.3% of adults in the United States being

affected [3-7] and threatening pandemic scale in the near future. But of vastly greater

concern is that over 79 million American adults have a condition of “prediabetes,” defined by

(1) impaired glucose tolerance/IGT (140 mg/dL to 199 mg/dL), (2) impaired fasting glucose/IFG (100 mg/dL to 125 mg/dL), or (3) at-risk A1C (5.7% to 6.4%) that puts them

at significantly increased risk for developing diabetes [1-6, 8], and alarmingly, it is known that over a 3- to 5-year period, prediabetics have a 5- to 15-fold higher risk of developing type 2 diabetes compared to people with normal blood glucose levels

[9]. This is an especially grave problem since treatment only prevents some of the dire complications of diabetes, usually failing to restore normal blood glucose

levels or to eliminate all of the adverse events associated with diabetes, entailing enormous and accelerating economic and social cost. And the cumulative data [10]

shows that the burden of diabetes continues to shift toward low and middle-income countries where almost 80% of diabetes deaths occur, precisely where there is

regrettable limited access to affordable treatment, and often insufficienteducation.

Exercise / Lifestyle In a seminal RCT of obese older adults [11],

exercise with weight loss improved glucose metabolism (both hepatic and peripheral

insulin resistance) and reduced visceral fat more than comparable weight loss without

exercise, and in a confirmatory RCT in prediabetics [12], all interventions

(antihyperglycemic medication monotherapy, antihyperglycemic medication with exercise,

and exercise training alone.

The Early ACTID RCT [13] compared physical activity (PA) of brisk walking for 30 minutes, 5 days per week (150 min/wk), with PA + diet in newly diagnosed diabetics,

found that A1C and insulin resistance improved, and use of diabetes medications were reduced for the diet and diet plus PA groups, which demonstrates that physical

activity itself added no additional benefit to an intense dietary intervention in


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which between 5% and 10% of body weight was lost, in agreement with other studies [14]. Similarly, in a meta-analysis [15] of ten large prospective studies (>190,000

diabetes-free-at-baseline subjects, followed from 2 to 23 years, with 8,932 cases of incident diabetes, it was found that all ten studies showed consistent outcomes,

namely a relative risk reduction of type 2 diabetes from 15% - 83%, with adherence to a healthy dietary pattern (high consumption of fruit and vegetables, whole grains,

fish, and poultry, and by decreased consumption of red meat, processed foods, sugar- sweetened beverages, and starchy foods) being associated with reduced risk of

diabetes development.

Trouble in Paradise: Prevention Woes and Pitfalls But the largest and arguably the most

compelling evidence for the preventive benefits of lifestyle

modification in the U.S. is that of the Diabetes Prevention Program

(DPP) [16], the first RCT to compare lifestyle and a pharmacologic

intervention to placebo, with weight loss established as the predominant

predictor of reduced diabetes incidence, at a 16% reduction in risk

per every kilogram of weight lost, although even those who achieved exercise goals only, not weight loss goals, also experienced significant reduction

(44%) in diabetes risk. And a systematic review [17] of (pancreatic) beta-cell function which controls the storage and release of insulin found that although

lifestyle modification reduces impaired glucose tolerance (IGT) progression to diabetes, both implementation and maintenance are difficult and complex, with 40–

50% of impaired glucose tolerance (IGT) subjects progressing to diabetes despite weight loss. This contrasts with pharmacological intervention with medications that

reverse known pathophysiological abnormalities, especially beta -cell dysfunction and insulin resistance, and uniformly prevent impaired glucose tolerance (IGT)

progression to diabetes, with a reduction of diabetes development of approximately50–70% from thiazolidinediones and 31% from metformin.

Unquestionably both obesity and physical inactivity represent critical risk factors for diabetes, causing insulin resistance with in turn places an increased insulin

secretory demand on beta-cells , and with obesity alone being the single most important factor responsible for the epidemic increase in diabetes over the last 2+

decades. Several robust lifestyle intervention studies [6,18-21] have demonstrated that diet/exercise regimens d ecreases progression to diabetes from impaired glucose

tolerance (IGT) via their improvement of insulin sensitivity and augmentation of insulin secretion , but as noted above, evidence [22] shows that implementation is complex and maintenance of weight loss/physical activity difficult to sustain over

long periods, something also demonstrated in the Diabetes Prevention Program (DPP),


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where weight was largely regained when the DPP ended [23] . And pharmacologically induced weight loss is also followed by weight regain when drug therapy is reverted

to placebo, despite continued dietary intervention [24] . Indeed, w eight regain is an undeletable characteristic of most weight loss programs, regardless of the type of

dietary intervention , so that efforts to translate the results of the Diabetes Prevention Program (DPP ) to clinical practice have proven uncommonly stubborn . Thus

in the FIN-D2D Trial [25] in Finland of 10,149 high-risk subjects in a diabetes prevention program designed to achieve 5–7% weight loss, a total of were enrolled ,

o nly one third of the subjects managed to successfully reduced their body weight by more than 2.5% , and the incidence of diabetes was reduced only 50–60% [18], entailing that almost half of all subjects (40–50%) with impaired glucose tolerance (IGT)

still progress to diabetes despite successful weight loss . This indicates that lifestyle intervention alone is insufficient to prevent the development of diabetes

in large proportions of subjects, in stark contrast to pharmacological therapy which uniformly and significantly reduces impaired glucose tolerance (IGT) / impaired

fasting glucose (IFG) progression to diabetes.

Methodological Borders and Limitations of Nutrition Interventions What we do know from nutritional studies is that diets rich in fruit and vegetables,

whole grains, and legumes, and low in red and processed meat, saturated fatty acids, and refined grains, protect from the development of diabetes [26], although note

that Individuals who consume a healthy diet are also often more active.

However I must point out that we know less than we think about the efficacy of nutritional interventions. That is because nutritional evidence largely originates

from observational studies with large uncontrolled confounding factors, and in addition rely on relatively insensitive food frequency questionnaires (FFQ).

Amazingly, one of the few clear outcomes of beneficial nutritional agents is that magnesium intake which is strongly evidenced as important in the prevention of

diabetes [27-29]. And I would add further that evidence from systematic review [30] strongly suggests that maintenance of weight loss is sustainable only via regular exercise that entails an additional expenditure of approximately 8.4 megajoules

(MJ) weekly, approx. 2000 kcal week. So if we look at the newest evaluative RCT [31] assessing the outcomes of the Diabetes Prevention Program (DPP) lifestyle

interventions, we find the sobering fact that the percentages of participants who achieved the 7% DPP-based weight-loss goal were 37.0% (coach-led group) and 35.9%

(self-directed group), leaving almost two-thirds of participants failing to achieve even that modest goal, and still higher percentages who are unlikely to maintain the loss into durable long-term gains. So the most recent evidence is even more sobering than the originally reported DPP data, and paints a picture of only modest benefit to

a clear minority of subjects with unlikely long-term or durable gains beingmaintained.

Sedentary Behavior: Case Pending Although epidemiological data seems to support this association, as per a systematic

review of prospective studies [32] which concluded that there was moderate evidence for a positive relationship between sitting time and the risk for Type 2 diabetes,


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with strong evidence for associations with all-cause and cardiovascular disease mortality, and a meta-analysis [33] finding that those in the highest sedentary

group had a 73% increased risk of metabolic syndrome compared with those in the lowest sedentary group, nonetheless I remind professionals that sedentary behavior,

predominantly TV viewing, itself clusters with other deleterious lifestyle practices, such as a poor diet, as a recent systematic review [34] has demonstrated

across 53 includable studies, where sedentary was clearly associated with several components of a unhealthy dietary behavior and a health-compromised diet, including

lower fruit and vegetable consumption, higher consumption of energy-dense snacks, drinks, and fast foods, and higher total energy intake. Thus, to date the

methodological limitations and probable confounding urge extreme caution in drawing any conclusion about the association of sedentary behavior itself and risk of

diabetes, as any superficial association may be secondary to underlying affiliated deleterious dietary behaviors.


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Pharmacological Preventive Interventions - Overview Our most effective pharmacological interventions for the prevention of diabetes via

forestalling the progression of IGT/IFG (impaired glucose tolerance/impaired fasting glucose) into diabetes are the thiazolidinediones (TDZ), GLP-1 (glucagon-

like peptide-1 analogs) and the biguanide metformin (Glucophage).

TDZ (Thiazolidinediones) As richly demonstrated above, although behavioral / lifestyle modification

(diet/exercise) is reasonably effective in preventing diabetes, weight loss is difficult to achieve and then maintain and, even when achieved, is often

insufficient to prevent progression of impaired glucose tolerance (IGT) to frank diabetes. However, the evidence supports to contention that pharmacological

interventions in combined with diet/exercise that improve and preserve beta -cell function and enhance insulin sensitivity represent the optimal preventive

interventions for high-risk individuals with impaired glucose tolerance (IGT) .Thiazolidinediones (TZD) are especially effective in preventing diabetes in

subjects with either or both IGT and IFG. In the Diabetes Prevention Program (DPP) metformin also delayed IGT conversion to diabetes , supporting an ADA Consensus

Conference Statement [35] recommending metformin for high-risk IGT individuals.

Here again I would urge caution and have elsewhere criticized the ADA Consensus. Why? I note that the documented efficacy of metformin in preventing impaired glucose

tolerance (IGT)" conversion to diabetes is just half (31 %) that observed withpioglitazone (62 - 72 %) [36]; I ignore here rosiglitazone given its unresolved

cardiovascular safety concerns , and based on my review I would advocate low-dose pioglitazone (15–30 mg/daily ) plus metformin (500–1000 mg/d) as representative of

optimal preventive intervention of impaired glucose tolerance (IGT) / impaired fasting glucose (IFG ), and I would add another strong motivation: the PROactive

Study [37] has demonstrated that pioglitazone may also decrease cardiovascular events.

Glucagon-like peptide-1 (GLP-1) analogs

Liraglutide, exenatide and glimipiride are potent insulin secretagogues, collectively known as glucagon-like peptide-1 (GLP-1) analogs, effectively

reducing PG levels in diabetes, as well as promoting weight loss [38] as shown in the LEAD Study [39], among many others, and also in the long-term Diabetes Research

Institute Exenatide Study [40] where exenatide produced durable HbA1c reduction, improved β-cell function induced progressive weight loss. To date a very rich body

of robust evidence has established that GLP-1 analogs are effective in treating diabetes, while reducing impaired glucose tolerance (IGT) conversion to diabetes, improving beta -cell function , promoting weight loss and improved cardiovascular

risk factors while not inducing undesirable hypoglycemia , all with convenience of administration (liraglutide once daily) , collectively making them near- ideal

agents for treating impaired glucose tolerance (IGT), allowing a highly optimal combination regimen of a GLP-1 receptor agonist for the preserv ation of beta -cell

function and promotion of weight loss , coupled with low-dose pioglitazone for ameliorat ion of i nsulin resistance and improvement of beta -cell function , possibly


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with an added weight loss promotion agent, this "anti-diabetic complex" regimen being maximally effective in preventing diabetes in people with impaired glucose

tolerance (IGT) or impaired fasting glucose (IFG) or both.

Reduction in CV Mortality and CV Events: More is Needed In a recent critical meta-analysis [41] of ten prospective RCTs totaling 23,152

patients, reporting all-cause mortality, and with a study size no less than 100 and with a least a one-year follow-up, of both pharmacological and lifestyle

interventions, no difference was observed between risk of all-cause mortality in the intervention versus control group, nor any difference in cardiovascular death, and

an observed trend towards reduction in fatal and non-fatal myocardial infarction was non-significant, with in addition only a borderline reduction in fatal and non-fatal

stroke. This and other supporting data demonstrates that although the interventions that were evaluable were mostly successful in reducing progression to overt

diabetes, the cardiovascular benefits intended from such a reduction failed to result in reductions in all-cause or in cardiovascular mortality, nor myocardial

infarction, and only marginal/borderline reduction in stroke incidence. We are left therefore with attainment of one more narrow goal (prevention of progression to

diabetes), without the full and critical attainment of significant reduction of the adverse cardiovascular sequelae of diabetes. Clearly therefore, even as of 2013, we

need more effective preventive interventions that both block progression to diabetes and provide a net gain of significant reductions in adverse cardiovascular

outcomes; I will report on these as they materialize and are critically appraised.


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What We are Missing What therefore contributes to the sorry state of truly extraordinary world-wide

efforts towards effective prevention of diabetes, against the distressing fact that diabetes and diabesity (diabetes and obesity) continue to grow dramatically, and in

the next two decades, explosively? We have already discussed above several contributory failures: (1) the failure of attainment of durable rather than just

limited and reversible weight loss, (2) the failure of consistent and reliable significant cardiovascular disease and mortality reductions; (3) the

methodological flaws of numerous interventional studies in diabetes prevention which fail to control for critical confounders, and (4) the fact the burden of

diabetes weighs disproportionately on non-affluent countries and populations who continue to have minimal clinical resources and educational outreach programs to

effectively deal with this growing pandemic. But, although a review of all contributing factors is beyond the scope of this review, I will briefly note two

components that are insufficiently addressed to date: (1) genetic response determinants, and (2) the increasingly critical role of Vitamin D metabolism and the

Vitamin D Receptor (VDR) in diabetes development. Genetics

In two ingenuous single nucleotide polymorphism (SNP) RCTs from the innovative Diabetes Prevention Program Research Group at George Washington University, it's

been shown that the AMPK subunit genes PRKAA1 and PRKAA2 appear to be genetic determinants of metformin response [42] and that two SNPs (BDNF rs6265, PPARG

Pro12Ala) were predictive of weight regain (WR), while the minor Ala12 allele at PPARG was associated with short- and long-term weight loss [43]. When cross-

confirmed (happening as we speak) and become commercially viable, these genetic response markers will prove invaluable in the optimal selection of candidates for

prevention interventions, and also allow us to focus more resources and therapeutic agents to those genetically dispose toward weight regain, and in addition allow us to

know to substitute TDZ and GLP-1 agents instead of metformin for those at genetic predisposition against metformin response, making the prevention of diabetes more a

personalized medicine than the current blunderbuss approach.

Vitamin D It is emerging strongly and clearly that Vitamin D plays

a vital role in diabetes pathogenesis: the Korean Prospective trial of Vitamin D deficiency in populations at high-risk for diabetes [44] found that

after adjustment for age, gender, blood pressure, lifestyles, family history, season, PTH (parathyroid

hormone), and high-sensitivity CRP (C-reactive protein), subjects with 25(OH)D deficiency had an increased risk of diabetes independently of body mass index (BMI), Homeostatic Model

Assessment - Insulin Resistance (HOMA2-IR), and IGI (Insulinogenic Index, which reflects acute phase insulin secretion). The fact that subjects with 25(OH)D

deficiency had an incidence of diabetes development 3.4 times that in those with sufficient levels, even after adjustment for obesity, dynamic measure of insulin


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resistance and pancreatic beta cell function, and other known diabetes risk factors strongly suggests that vitamin D metabolism plays a critical role in the

pathogenesis of diabetes independently of other known risk factors.

This has been confirmed in a meta-analysis establishing a strong inverse association between circulating 25(OH)D concentrations and risk of incident diabetes, an

association that remained in this new meta-analysis of prospective trials under the European Prospective Investigation into Cancer (EPIC) and Nutrition–Norfolk study

[45] after adjustment for critical relevant confounding factors.

Furthermore I note that both cross-sectional [46,47] and longitudinal studies like the recent MRC Ely Prospective Trial [48], the PROMISE Cohort Study [49], the

Karolinska Institutet Study [50] and the Australian Diabetes, Obesity and Lifestyle study [51] suggest that this Vitamin-D-Diabetes association is in part founded on

the demonstrated significant inverse association between serum 25(OH)D and diabetes or impaired glucose metabolism.

However I note from my critical appraisals that several studies, including the

Karolinska Institutet Study [50], the MRC Ely Prospective Trial [48] and the Australian Diabetes, Obesity and Lifestyle study [51] failed to adjust for dynamic

baseline glycemic measures of insulin secretory function or insulin sensitivity, something that is finally and effectively remedied for the first time in the Korean

Prospective trial [44] that decisively demonstrated the independence of the 25(OH)D level association with diabetes from baseline potential diabetes risk factors of

insulin secretion and sensitivity, an association maintained AFTER adjusting for HOMA2-IR, IGI, and obesity.

Furthermore, insulin resistance itself is now known to be associated with vitamin D

insufficiency [48], including as confirmed in systematic review and meta-analysis [52] and in addition, Vitamin D appears to have a direct effect on insulin

sensitivity via stimulation of insulin receptor expression [53]. Some data from a contrary RCT [54] appears not wholly consistent, but nonetheless stands against the

weight of cumulative evidence; see for instance the meta-analysis [55] of 16 studies where the odds ratio for diabetes was 1.50 for the bottom quartile compared to the top

quartile of 25(OH)D along with the associated prospective cohort study confirming the association of low plasma 25(OH)D with increased risk of diabetes, and the

University of Missouri RCT [56] concluding that increased circulating concentrations of 25(OH)D are associated with improved markers of insulin

sensitivity and resistance, among many other [57-62].

Methodology of this Review A search of the PUBMED, Cochrane Register of Controlled Trials, MEDLINE, EMBASE,

AMED, CINAHL, PsycINFO, (WoS) Web of Science, BIOSIS, LILACS and Scirus databases was conducted without language or date restrictions, and updated again current as of

date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical

feed sources as returned from Terkko (provided by the National Library of Health


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Sciences - Terkko at the University of Helsinki). A further "broad-spectrum" science search using Scirus (410+ million entry database) was then deployed for resources

not otherwise included. Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses

and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software.


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Diabetes Prevention - Promise and Limitations: A Review

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